The formulation of therapeutic proteins, such as antibodies, is often a challenge given the numerous desirable properties that the formulation must have to be economically and therapeutically successful, e.g., stability, suitability for administration, concentration. During manufacturing, storage, and delivery, therapeutic proteins have been known to undergo physical and chemical degradations. These instabilities can reduce the potency of the protein and increase the risk of adverse events in patients, and, therefore, significantly impact regulatory approval (see, e.g., Wang et al. J. Pharm. Sci. 96:1, 2007). As such, a stable protein formulation is essential to the success of a therapeutic protein.
To be effective, many therapeutic proteins require the administration of high doses, which, ideally, are formulated in high concentration formulations. High protein concentration formulations are desirable as they can impact the mode (e.g., intravenous vs. subcutaneous) and frequency of administration of the drug to a subject.
Despite the benefits of high protein concentration formulations, formulating high concentration therapeutic proteins presents numerous challenges. For example, increasing protein concentration often negatively impacts protein aggregation, solubility, stability, and viscosity (see, e.g., Shire et al. J. Pharm. Sci. 93:1390, 2004). Increased viscosity, which is a very common challenge for high protein solutions, can have negative ramifications on administration of the formulation, e.g., felt pain and burning syndromes and limitations in manufacturing, processing, fill-finish and drug delivery device options (see, e.g., Shire et al. J. Pharm. Sci. 93:1390, 2004). Even for therapeutic proteins having common structural features, e.g., antibodies, approved formulations to date have had varying ingredients and ranges of concentrations. For example, the anti-CD20 antibody Rituxan is formulated for intravenous administration at a concentration of 10 mg/mL, while the anti-RSV antibody Synagis is formulated for intramuscular administration at a concentration of 100 mg/mL. Thus, high protein formulations, especially antibody formulations, which can be used for therapeutic purposes remain a challenge.
Another challenge associated with therapeutic proteins, such as antibodies, is drug delivery. While self-administering devices allow patients to avoid unnecessary trips to medical facilities to receive treatments, patients' self-awareness and fear of the pain associated with self-administration may frequently impact self-administered drug delivery. Moreover, formulations having high concentrations of protein may have high viscosity resulting in increased pain upon delivery, particularly for subcutaneous administration. Thus, there is especially a need for high concentration formulations that reduce pain associated with drug delivery (e.g., self-injection).
Accordingly, there is a need for stable, high concentration protein formulations that provide dosing and administrative advantages, particularly with respect to a decrease in pain for the patient and/or improved bioavailability.